N-amino-benzamidines

ABSTRACT

Compounds of the formula WHEREIN R is hydrogen, alkyl, acyl, phenyl-lower alkyl, carbamoyl, benzoyl, R1 is lower alkyl, pyridyl, naphthyl, or cycloalkyl, R2 is phenyl or substituted phenyl, and R3 and R4 are hydrogen, lower alkyl, phenyl or phenyl-lower alkyl, or taken together are alkylene, possess anti-inflammatory activity.

United States Patent 1 Bandurco et al.

[111 3,715,396 [45] Feb. 6, 1973 [54] N-AMINO-BENZAMIDINES [75] Inventors: Victor Bandurco, Huntington Station; Bill Elpern, White Plains; James R. Shroff, Bronx, all of N.Y.

[73] Assignee: USV Pharmaceutical Corporation [22] Filed: Nov. 4, 1969 [21] Appl. No.: 874,083

[56] References Cited UNITED STATES PATENTS 3,458,500 7/1969 Davis ..260/564 R X OTHER PUBLICATIONS R. Smith, Open Chain Nitrogen Compound, Vol. I, pp. 173-174 (1965) S. Wagner and look, Synthetic Organic Chemistry, pp. 647 (1965) Primary Examiner-Howard T. Mars Assistant Examiner-Gerald A. Schwartz Att0rney-Leon E. Tenebaum ABSTRACT Compounds of the formula,

w R; R

NI 'I-C Rz R4/ N-R1 wherein R is hydrogen, alkyl, acyl, phenyl-lower alkyl, carbamoyl, benzoyl, R is lower alkyl, pyridyl, naphthyl, or cycloalkyl, R is phenyl or substituted phenyl, and R and R are hydrogen, lower alkyl, phenyl or phenyl-lower alkyl, or taken together are alkylene, possess anti-inflammatory activity.

5 Claims, No Drawings N-AMINO-BENZAMIDINES This invention relates to new organic compounds having valuable pharmacological activity and to and their pharmaceutically acceptable, non-toxic acid addition salts, wherein R is hydrogen, alkyl, alkenyl, acyl, carbamoyl phenyl-lower alkyl, substituted phenyl-lower alkyl, benzoyl, or substituted benzoyl;

R is lower alkyl, phenyl, pyridyl, naphthyl, substituted phenyl, or cycloalkyl;

R is phenyl or substituted phenyl, and

R and R are hydrogen, lower alkyl, phenyl, or phenyl-lower alkyl, or R and R may be taken together to form an alkylene group having from four to six carbon atoms.

The R alkyl and alkenyl groups, which may be branched or straight chained, contain up to 12 carbon atoms and include such radicals as methyl, ethyl, ipropyl, amyl, allyl, octyl, 2-ethylhexyl, decyl, dodecyl and the like. i

The substituted phenyl, phenyl-lower alkyl or benzoyl may carry such substituents as lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, sulfonamido, or nitro.

The lower alkyl and lower alkoxy groups may be straight chained or branched and contain from one to six carbon atoms.

The cycloalkyl groups contain from five to seven carbon atoms in the ring which may be substituted with lower alkyl groups.

Preferably, R is benzyl or substituted benzyl, R is lower alkyl, preferably isobutyl, R is phenyl, and R and R are methyl.

The pharmaceutically acceptable non-toxic acid addition salts include salts of inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric, and organic acids such as acetic, propionic, glycolic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, ascorbic, benzoic, hydroxybenzoic, aminosalicylic, cinnamic, mandelic, benzenesulfonic, toluenesulfonic, nicotinic, isonicotinic and the like.

According toa process of this invention, the N- amino-benzamidines were prepared by refluxing in an inert solvent a benzimidoyl chloride of the formula with a hydrazine of the formula wherein R, R,, R R and R are the same as above. Preferably, twice the molar quantity of the hydrazine was used, and the resulting free base was then distilled. In a variation of the above process the reactants were used in a 1:1 molar ratio, and the product was obtained as the hydrochloride which could be converted to the free base by treatment with ammonia or another suitable alkaline agent. If R is hydrogen, then the resulting N-amino-benzamidine may be treated with a compound,

wherein R is the same as above except hydrogen, and the desired product can be obtained.

The hydrazines are commercially available. The benzimidoyl chlorides are readily prepared by treating an amide of the formula with a halogenating agent such as SOCl, or lCl, in accordance with the method described in Organic Syntheses, Coll. Vol. 4, page 383.

The invention will be more fully illustrated in the examples which follow, which examples are given by way of illustration and are not to be considered as limiting.

EXAMPLE I N-Isobutyl-N-(3-trifluoromethylbenzyl)-N- dimethylaminobenzamidine A mixture of 21.9 grams (0.] mole) N'-isobutyl-N- dimethylaminobenzamidine and 19.4 grams (0.1 mole) S-trifluoromethylbenzyl chloride in ml. dry acetonitrile was refluxed for 48 hours. The solvent was removed and the residue neutralized with 10 percent sodium hydroxide to yield 25.0 grams of the free base. The free base was subjected to fractional distillation and the fraction distilling at 120-l22C/0.05 mm. was collected. The oil solidified on standing to a yellow solid. Wt. 8 grams (22.3 percent), M.P. 38-40C EXAMPLE ll N'-lsobutyl-N-dimethylamino-benzamidine To a solution of 19.6 g. (0.1 mole) N-isobutylbenzimidoyl chloride is 50 ml. toluene, was added dropwise, over a period of 20 min., 12.1 g. (0.2 mole) unsymmetrical dimethyl hydrazine in 120 ml. toluene. The reaction mixture was maintained at 5-10C during the addition. The resulting white suspension was stirred for 1 hr. at 5-i5C and then at room temp. for approximately 16 hrs. A yellow solution with a small amount of gelatinous solid was obtained. The solid was filtered off, and the solvent removed from the filtrate. The residue, a yellow oil weighing 220 g., was distilled and the fraction distilling at 88-9lC/0.275 mm. was collected. The free base, a yellow liquid, weighed 19.3 g., n,,"=l.5l90. The hydrochloride was prepared by dissolving l7 g. of the free base in ml. ethyl acetate, cooling to 10C and bubbling in dry hydrogen chloride (28.5 to give 187 g. ofa white product, m.p. 124"-12 5C.

In accordance with the procedures described above and set forth in the examples, the additional compounds in the table below were prepared.

3,4-Dichlorobenzyl 4-Cyanobenzyl J-Methylbenzyl 3 ,4-Dimethylbenzyl 3-Trifluoromethylbenzyl S-Trifluoromethylbenzy 3'Trifluoromethylbenzyl 3-Trifluoromethylbenzyl 4-Nitrobenzyl B-Nitrobenzyl 3-Nitrobenzyl 3-Nitrobenzyl ZIIIIIIIIIIII: n

n-But 3-Methylpentyl Benzyl a-Phenethyl B-Phenethyl 3-Propylghenyl 4-Fluoro enzyl 3.4-Dichlorobenzyl 4-Methylbenzyl 2-Cyclohexylethyl IIIIIIIIIIII:

i-But CJI i-But C,H

i-But C,H,

i-But C,H,

i-But C ll,

l-But C l-l,

i-But C ll i-But C,H,

i-But C,H,

i-But C li,

i-But C l-l i-But C,H,

i-But C H,

l-But C l-l i-But C ll,

i-But 4-F-C l-l.

l-But 4-Me-C,H,

i-But 2-Me-C H i-But C l-l,

i-But C H,

i-But 4--Me-C,H i-But Z-Me-C H Et C,H

Me C H,

i-But C H i-Pr C H, a-Naph C H Cyclohex C H n-But C H,

Pr C,H, Me Pr C H Me Pr C ll, Me Pr C H, Me Pr C,H, Me Pr C H, Me Pr C l-l, Me Pr C,H, Me Pr C,H Me Pr C,l'l Me Pr CJI Me Pr C,H, Me Me C.H, C,H, Pr C,H, C,H, i-But C,H, C H, i-Am CJ'l, C B, Hex C H, C H Cyclohex C l-l, C H C H, C,H, C,H, Me C H,

i-But C H,

i-But C.H,

i-Am C ll,

Hex C H,

Me Me H C clohex C,H, Pentamcthylene Me Me H e a a Hexamethylene Me Me H i-But cm, Hexamethylenc Me Me H Pr C 11, Hexamethylene Et E H Cyclohex C H Hexamethylene Me Me Me Me 5 Me Me The compounds of this invention are potent antimw m flammatory agents showing a reduction in inflammation by the standard carrageenan, cotton pellet and UV Me Me erythema tests. At doses of 30 mg./kg. in the standard a: m: carrageenan test reductions up to 86 percent were obe Me tained, while at 90 mg./kg. reductions up to 100 per- Me Me cent were obtained. m a Certam compounds of this invention, particularly wherein R is H, R is isobutyl, R and R are lower alkyl, Me Me and R is phenyl or o-tolyl showed strong hypoglycemic Me Me l d l 1 l Me Me activity in lowering the b 00 sugar eve s m g ucose Me Me primed rats. At 100 mg./kg. p.o. the compound where w '6 R is o-tolyl and R and R are methyl gave a 44 percent reduction, while the compound where R is phenyl and Me Me R and R are ethyl gave a 33 percent reduction at 50 Me Me m /k 0 Me Me Me Me The novel compounds of this invention can be combined with solid or liquid pharmaceutical carriers and Me Me formulated into tablets, powders, or capsules or dis- Me Me solved in suitable solvents for oral and parenteral ad- Me Me ministration for human or veterinary use.

We claim Me Me 1. A compound of the formula Me Me Me Me Me Me Me Me f{ Me Me \N Ft Pr NC-Rn m: fi Rt N-Rl Me Me Me Me m: n: wherein Me Me R is hydrogen, alkyl, containing up to 12 carbon m m atoms or alkenyl containing up to 12 carbon 8 e Me Me R is lower alkyl, phenyl, naphthyl, or cycloalkyl; Me Me R lS phenyl, lower al kyl-phenyl, halophenyl, lower Me alkoxy-phenyl, or trifluoromethylphenyl; and m R and R are hydrogen, lower alkyl, phenyl, phenyllower alkyl, and may be the same or different, or Me R and R, may be joined together to form an al- Me Me kylene having from 4 to 6 carbon atoms; Me or salts thereof of pharmaceutically acceptable acids. 035 2. A compound according to claim 1 wherein R and 2 R are methyl. C.H, 3. A compound according to claim 2 wherein R is c n b I CHB ISO uty. c n, 4. A compound according to claim 3 wherein R is Pentamethylene h L 5. A compound according to claim 4 wherein R is Pentamethylene hydrogen. Pentamethylene Pentamethylene 

1. A compound of the formula wherein R is hydrogen, alkyl, containing up to 12 carbon atoms or alkenyl containing up to 12 carbon atoms; R1 is lower alkyl, phenyl, naphthyl, or cycloalkyl; R2 is phenyl, lower alkyl-phenyl, halophenyl, lower alkoxy-phenyl, or trifluoromethylphenyl; and R3 and R4 are hydrogen, lower alkyl, phenyl, phenyl-lower alkyl, and may be the same or different, or R3 and R4 may be joined together to form an alkylene having from 4 to 6 carbon atoms; or salts thereof of pharmaceutically acceptable acids.
 2. A compound according to claim 1 wherein R3 and R4 are methyl.
 3. A compound according to claim 2 wherein R1 is isobutyl.
 4. A compound according to claim 3 wherein R2 is phenyl. 